Pharmacological inhibition of TXNRD1 attenuates psoriasis-like dermatitis by suppressing keratinocyte proliferation and NF-κB signaling.

Psoriasis is a chronic inflammatory skin disease characterized by excessive keratinocyte proliferation and immune activation. Thioredoxin reductase 1 (TXNRD1), a key enzyme of the thioredoxin antioxidant system, regulates cellular redox balance and inflammatory signaling; however, its functional role in psoriasis remains unclear. Here, we demonstrate that TXNRD1 expression is markedly upregulated in lesional skin from psoriasis patients and in imiquimod-induced psoriasis-like dermatitis in mice. Genetic deletion of TXNRD1 in keratinocytes significantly suppressed cell proliferation, reduced pro-inflammatory cytokine production, and diminished chemotactic activity toward CD4+ T cells in vitro. Importantly, topical administration of the TXNRD1 inhibitor TRi markedly alleviated psoriasis-like skin inflammation in vivo, as evidenced by reduced epidermal hyperplasia and decreased CD4+ T cell infiltration. Mechanistically, TNF-α and IFN-γ induced TXNRD1 expression and activated NF-κB signaling in keratinocytes. TXNRD1 deficiency significantly attenuated TNF-α/IFN-γ-induced NF-κB phosphorylation, leading to reduced chemokine expression and impaired T-cell recruitment. These findings identify TXNRD1 as a critical regulator of keratinocyte-driven inflammatory responses and provide pharmacological evidence supporting TXNRD1 as a potential therapeutic target for psoriasis.